Glucose 'flowz in' the PCT
| Metformin | Biguanide | Insulin sensitiztion Reduce hepatic gluconeogenesis. | GI side effects Lactic acidosis (risk in renal/liver/heart failure – contrindications) No weight gain May reduce apetite, STOP when eGFR < 30 | Reduced GI B12 absorption The usual first line agent, can be combined with other | Lower FBS by about 50 mg/dL Lowers HbA1C by about 1% |
| Empagliflozin Dapagliflozin Canagliflozin | SGLT inhibitors | Inhibit the coupled reabsorption of sodium and glucose from the proximal tubules (+ other renal effects) | Dehydration Genital candidiasis (but not bacterial UTI),Can precipitate DKA (increase production of ketones) | Wonder drug! Decreases weight Improve renal dysfuntion – renoprotective Reduce atherosclerotic events! Reduce risk of heart failure | ?More potent glucose lowering than metformin(values given in K&C). Weight loss of 2-4 Kg over 1 year |
Sources:

• SGLT-2 inhibitors cause fungal but not bacterial UTI:Source

SGLT2i decreases available carbohydrate and drives metabolism towards more efficient ketone-based energy sources, leading to weight loss, decreased tissue adiposity, and increased serum concentrations of β-hydroxybutyrate. Source

[!INFO]
Read this Source for a good overview. (it's long)

Overview of hypoglycaemic agents in CKD

The sulfonylureas are strongly protein bound, particularly to albumin. Thus, elevated plasma drug levels cannot be efficiently reversed by hemodialysis. Furthermore, displacement of these drugs from albumin by beta blockers, salicylates, and warfarin can lead to hypoglycemia due to increased plasma concentration of the free sulfonylurea.
Sulfonylureas which can be used in CKD are

1. gliclazide
2. glimepiride
3. glipizide

SGLT2 inhibitors:

• There is substantial evidence to support a reduced risk of ESKD, cardiovascular death, and hospitalization for heart failure. Source
• The cardiovascular and kidney benefits of SGLT2i are independent of the antihyperglycemic effect, which attenuates with lower eGFR.

SGLT2 inhibitors are safe and 'recommended' when eGFR is > 30 BUT below this, they are not recommended because of their low efficacy in this state.

GLP-1 agonists:

• Preferred in stage 4 CKD because of cardiac and renal protective effects.
• Can also be used in stage 5.
• SGLT-2 inhibitors (esp. if eGFR < 30) - Because of low efficacy and weak effect of lowering HbA1C.

- If any of it escapes the clot, the plasmin is inactivated by PAI-1, to prevent *digestion of tissues!* 😱😱 (PAI 1- plasminogen activator inhibitor 1)
- Technically, PAI is an inhibitor of plasminogen activator. 
- Direct inhibition of plasmin itself is by alpha2-antiplasmin. 
- 

Fibrinolytic system and drugs

• Plasminogen floats around in plasma. If it finds fibrin, it binds to it.
• It binds to fibrin in the inactivated form (plasminogen) but requires activation by tissue plasminogen activators which diffuse into the clot from the plasma.
• Once activated, plasmin degrades fibrin and several other clotting cascade proteins.
• Any plasmin which escapes the clot is quickly inactivated by plasmin inactivators before it can damage other tissues.

Plasminogen is activated mainly while it is bound to fibrin because fibrin has receptors for both plasminongen AND plasmin activators.
Similarly, activated plasmin is protected from inactivation while it is bound to fibrin. If it breaks free into the plasma, it's more vulnerable to inactivation.

Fibrinolytic drugs

#2020BSQ-NOV/Q24

1. Streptokinase: a streptococcal product that happens to activate plasminogen.
   1. Can't be used > 4 days after first dose due to formation of inactivating antibodies.
   2. Can cause hypotension due to kinin formation.
2. Alteplase and duteplase: recombinant tissue plasminogen activator
   1. Specific to fibrinogen-bound plasminogen (and not free plasminogen). Therefore, clot selective
   2. Not antigenic
   3. Short half life -> must be given as infusion
      1. Given as a bolus followed by two drips.
   4. Reteplase is similar but longer half life -> can be given as boluses.
      1. Given as two boluses 30 minutes apart.
3. Tenecteplase and reteplase are 3rd generation agents. Better risk : benefit ratios than alteplase.

Alteplase improves survival over streptokinase.
Reteplase similar efficacy alteplase but reteplase is easier to use.
Tenecteplase = similar efficacy to alteplase AND lower rate of non cerebral bleeding events. Given as a single bolus (not an infusion)

Antifibrinolytics

Tranexamic acid inhibits activation of plasminogen.

• Both are vitamin K dependent anti-clotting factors. They inactivate factor Va and factor VIIIa.
• Protein C also inactivates PAI-1.
  • Inactivation of this plasminogen activator inhibitor -> plasminogen activation -> promotion of fibrinolysis.
• Many mutations can cause reduced function; therefore for diagnosis, assays measure protein concentration.

Fat embolism

#2020BSQ-NOV/Q54
Sources:

• Source

Fat embolism syndrome = FES
There are two theories for the pathogenesis (which are not mutually exclusive):

1. Mechanical damage to vessels causes fat globules to enter the circulation
2. Toxic metabolites of these fat globules (OR flat globules released into the circulation because of a response to trauma / stress) promotes inflammation
   1. FES is associated with elevated CRP, cytokines, phospholipase A2, elevated circulating free fatty acids.
   2. This may explain the usual delay of 24-72 hours from inciting events to manifestation of FES.
      Most commonly associated with femur and pelvic fractures.
      Can occur with trauma without fractures as well.

Symptoms:

• There is a triad of skin, brain and lung dysfunction.
• Onset 24 - 72 hours after insult.
• Lungs -> Hypoxaemia
• Brain -> confusion, altered consciousness and seizures.
• Skin -> Nonpalpable petechial rash in the chest, axilla, conjunctiva, and neck. (occurs in < 50%)
• Associated features: Thrombocytopaenia, anaemia (both are very common), lipiduria (rare), fever, coagulation abnormalities, hypofirinogenaemia. Apparently, the cause of anaemia is unexplained. Source
• Also Right ventricular dysfunction and myocardial depression.
• CXR: diffuse pulmonary infiltrate.
  Diagnostic criteria:
• Gurd and Wilson diagnostic criteria [Source](https://www.ncbi.nlm.nih.gov/books/NBK499885/

Management:

• For patients without sickle cell disease, management is supportive with oxygen therapy.
• FES in [[2021 General Medicine#Sickle cell disease complications]](where (where (where (where (where (where (where (where (where needs urgent exchange transfusion.
• Routine use of steroids (specially prophylactically) is not recommended.

Prognosis: Most recover with no long term sequelae.

Cancers associated with smoking

#2020BSQ-NOV/Q59
Respiratory:

• Nasal cavity and paranasal sinuses
• Larynx, pharynx, trachea, bronchus
• Lung (obviously)
  GI:
• Oral
• Oesophagus
• Gastric
• Pancreatic
• Colorectal
  Urinary
• Kidney
• Renal pelvis, ureter
• Bladder
• Penile
  Others:
• Mesothelioma
• Myeloid leukemia

[!INFO] Smoking may be protective against thyroid cancer!
pooled analysis of five prospective studies suggested that cigarette smoking reduces the risk for PTC and probably FTC in 30-40% of subjects. Source

Lesions of pyramidal and extrapyramidal tracts

Snell seems to be confused about pyramidal and extrapyramidal tracts; don't read that.

Pyramidal tracts: The upper motor neurons; start in the cortex and then to the cranial nerve nuclei or in the pyramids to the anterior horn cells.
Signs of pyramidal dysfunction:

• Pyramidal drift
• Weakness and loss of skilled movements. Distribution of weakness can be distinctive.
  • Hemiparesis - weakness of one half of the body
  • Hemiplegia - complete loss of power
• Increase of tone (acutely there is flaccid paralysis replaced within several days by spasticity) (see spasticity VS. rigidity below)
  • Including clasp knife effect.
  • Exaggerated tendon reflexes
• Loss of superficial receptors
  • Development of extensor plantar response.
  • Loss of superficial abdominal reflex
  • Loss of cremasteric reflex

Extrapyramidal system(EPS):

• Another term for the [[General medicine 6-Neurology#Summary of Parkinson's pathology|basal ganglia]] motor systems. Overall function is modulation of movement.

Lesions of the EPS cause either one or both of

• Bradykinesia (reduction) or akinesia (loss) of movement and ridigity. (eg Parkinson'd diseas)
• hyperkinesia (tremmor, chorea, tics, myoclonus, dystonia) (eg. Huntington's disease)

Source <- not many other sources on this.

Cerebellar signs

A pneumonic to remember some of the cerebellar signs is DANISH.

• Dysdiadokinesia / dysmetria
• Ataxia
• Intention tremor
• Speech - slurred or scanning
• Hypotonia
  Source

1. Acute chest syndrome: Infection, pulmonary infarction from occlusion or [[2020-NOV-BasicSciences#Fat embolism|Fat embolism]] from necrotic bone. (chest pain with fever, SOB, hypoxia, with new CXR changes) (Mx is with oxygen antibiotics and exchange transfusion if poor response to initial measures).

#2021SBR-NOV/Q13
#2020BSQ-NOV/Q50

• Acute (<2 weeks), mild illness(just fever and cough)
  Eosinophilic infiltration of various organs; heart is particularly involved.

#2020BSQ-NOV/Q50

parasite has a free living cycle and parasitic cycle.
So adult worms can be found in the environment and the intestinal lumen of hosts.
Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Eosinophilia(+).
Can cause [[2021-SBR-November#Loffler syndrome / Loeffler syndrome | Loeffler syndrome]]

Echinococcosis

#2020BSQ-NOV/Q50
? Dog tape worm
A 2-7mm long small tape form whose definitive host is the dog.
Intermediate host is animals like sheep.
Sheep tissues have cysts which are infective when ingested by a dog.
The adult forms in the dog then shed eggs with foeces which are usually ingested by the sheep, but can also be ingested by humans.
One ingested, the eggs hatch the the larvae penetrate the intestinal wall and take up residence in the tissues.
In the tissues, they from hydatid cysts.
The cysts usually grow for many years and are asymptomatic until they cause symptoms due to pressure effects.
However, if a cyst ruptures, it can cause analphylaxis, or a milder fever, and dissemination of the parasites within.
Treatment: Surgery or less invasive procedures like PAIR (percutaneous aspiration, injection of chemicals and reaspiration).

Trichinellosis

#2020BSQ-NOV/Q50

Image of skeletal muscle encysted and liberated trichinella parasite.

• Trichinella is acquired by eating undercooked meat which contains the cysts.
• They initially colonize the GI tract -> gastrointestinal symptoms.
• Excystation occurs after passage through gastric acid. Excested larvae develop into adults which produce larvae which migrate through the intestinal wall and encyst in host skeletal muscle about 1 week later after infection.
• Clinical features are somewhat distinctive: periporbital oedema, facial oedema, conjunctivitis, fever, splinter haemorrhage, rashes, and peripheral eosinophilia.
• Occasional life threatening manifestations are CNS involvement, myocarditis, and pneumonitis.

Treatment:
Albendazole and mebendazole for about 14 and 10 days respectively. Treatment should be started within first few days of infection, or else, larvae will migrate into skeletal muscle and treatment will not completely eliminate the infection.

Trichiuris

Trichiuris trichiura - the human whipworm

• Maginified endoscopic images of a trichiuris parasite in the colon. Source
• The adult is about 4 cm in length.
• The adult worms embed into the mucosa with the anterior part and live in the caecum and ascending colon, shedding thousands of eggs per day. Their lifespan is about 1 year.
• Unembryonated eggs enter the soil with faeces and become infective only after about 15 to 30 days.
• Embryonated eggs are the infective stage and are transmitted by the faeco-oral route.
  Symptoms
• Commonly asymptomatic
• Heavy infestations in children can cause abdominal pain, diarrhoea and rectal prolapse, impaired growth, anaemia, impaired cognitive develoment.
• Heavy infections can cause stool with mucous and blood. (?probably due to the mucosal attachment of the worms) and rectal prolapse.

Diagnosis:

• By microscopic identification of worm eggs in faeces.

Treatment:

• Albendazole, mebendazole or ivermectin for 3 days. Effectively treated.